Nonsyndromic orofacial clefts (OFCs) of the lip with or without cleft palate (CL/P) or of the palate only (CPO) comprise a significant proportion of human birth defects (about 1/700 live births worldwide). OFCs require surgical, nutritional, dental, speech, medical and behavioral interventions, and thus impose substantial public health, economic, and personal burdens. During the previous funding periods of this project, we achieved all our delineated goals and unequivocally established the rich phenotyping paradigm that our research group has developed over the last decade. Our subclinical phenotyping approach has the potential to help define mechanisms that lead to OFCs and provide improved prediction of individual risks for these defects. Subclinical expressions of OFC (e.g., subtle speech abnormalities) that are distributed within affected families can reveal clues about etiology. Numerous genes/loci have now been identified for overt OFC, based largely on recent genome-wide association studies resulting from the present funding period. The current grant proposal is a renewal of grant #R01-DE016148, now in its second funding period. The overarching goal of this renewal remains consistent, i.e. to incorporate subclinical phenotypic features into etiologic studies of OFCs in an effort to both improve our understanding of genetic and other risk factors underlying these birth defects and to facilitate the translation of this improved understanding to clinical applications. The specific aims for this renewal follow directly from the discoveries of the previous funding periods, i.e. to: (1) further characterize patterns of subclinical OFC phenotypes in cleft families; (2) uncover the genetic basis of overt forms of OFC; (3) discover the genetic basis of subclinical OFC-related phenotypes. Our previous findings also serve to underscore the fact that different populations/ethnicities, as well as different forms of clefting, are likely characterized by distinct etiological profiles. Our present proposal aims to address this issue directly by recruiting understudied, yet etiologically informative, populations (i.e., Sub-Saharan Africans) and less well understood forms of clefting (i.e. CPO). We will continue our successful genetic studies in OFC families, incorporating both well-established and novel subclinical phenotypes into formal gene identification approaches. Our proposal will potentially translate the findings from human genetic studies into strategies that can be eventually assessed through robust clinical studies, with the ultimate goal of improving the standard of care of individuals with OFCs.